Anxiety disorders, one of the most prevalent psychiatric illnesses in the general community, represents a group of emotional states consisting of psychophysiological responses to anticipation of unreal or imagined danger which are not a result of physical disorders, drug abuse or other psychiatric conditions (Anxiety Overview, Market Research Reports, 2001; Briley M and Moret C, Present and Future Anxiolytics, Drugs, 2000, 3 (7), 695-699; Stein M B, Neurobiological perspectives on social phobia: From affiliation to zoology, Biol. Psychiatry, 1998, 44 (12), 1277-1285; Newburn G, Psychiatric disorders associated with traumatic brain injury. Optimal treatment, CNS Drugs, 1998, 9 (6), 441-456; Lidberg L, et. al., Suicide attempts and impulse control disorder are related to low cerebrospinal fluid 5-HIAA in mentally disordered violent offenders, Acta Psychiatr. Scand., 2000, 101 (5), 395-402; Van Ameringen M, et. al., Drugs in development for social anxiety disorder: more to social anxiety than meets the SSRI, Expert Opin. Invest. Drugs, 2000, 9 (10), 2215-2231; Zhuang X, et. al., Altered emotional states in knockout mice lacking 5-HT1A or 5-HT1B receptors, Neuropsychopharmacology, 1999, 21 (2S), 52S-60S).
Anxiety disorders include, but are not limited to, generalized anxiety disorders, panic disorders (including those with or without agoraphobia and symptoms of anticipatory anxiety, recurrent sleep panic attacks (not nightmares) and distressing symptoms (eg, dyspnea, tachycardia, palpitations, headaches, dizziness, paresthesias, choking, smothering feeling, nausea and bloating) in association with feelings of impending doom (i.e., an alarm response)), impulse control disorders (such as obsessive-compulsive disorder (OCD), bulimia, episodic dyscontrol, trichotillomania, compulsive gambling and kleptomania), phobic disorders (those disorders with feelings of displacement not due to impaired cognitive abilities (social phobia and avoidant personality disorders, including both global social phobia and specific social phobia, simple phobia, agoraphobia, apiphobia, tropophobia, astrapophobia, triskaidekaphobia, blennophobia, thalassophobia, claustrophobia, spheksophobia, cynophobia, sciophobia, decidophobia, eletrophobia, scholionophobia, eremophobia, pyrophobia, gamophobia, pnigerophobia, ophidiophobia, odynophobia, nyctophobia, ochlophobia, musophobia, keraunophobia, katagelophobia, kakorraphiophobia, hydrophobia, gynophobia, gatophobia, gephyrophobia, acrophobia or amathophobia)), posttraumatic stress disorder (PTSD), dissociative states (including amnesia, somnambulism, dissociative identity disorder or depersonalization), presurgical anxiety states, postsurgical anxiety states or other medical or psychiatric induced anxiety conditions (including, but not limited to, anxiety resulting from traumatic brain injury, chronic pain disorders or other chronic disease conditions).
OCD is one of the most common psychiatric disorders, occurring in 2-3% of the U.S. population. In OCD, the irrational idea or the impulse persistently intrudes into awareness with obsessions (constantly recurring thoughts) and compulsions (repetitive actions). Since dysfunctions of the serotonergic system have been particularly implicated in OCD, traditional pharmacological interventions have included SSRIs (selective serotonin reuptake inhibitors), clomipramine, MAOIs (monoamine oxidase inhibitors) and clonazepam. Approximately 60% of OCD patients respond to serotonergic drugs in doses equivalent to those used for depression such as sertraline, paroxetine, fluvoxamine and buspirone. In addition, there is clinical evidence that epilepsy and OCD are associated disorders on the basis that the abnormal neuronal firing present in both disorders can be regulated by anticonvulsants with a broad spectrum of activity. For example, OCD patients, even those with refractory OCD, showed clinical improvement after treatment with anticonvulsant drugs such as carbamazepine and gabapentin (Iwata Y, et. al., Carbamazepine augmentation of clomipramine in the treatment of refractory obsessive-compulsive disorder [letter], J. Clinical Psychiatry, 2000, 61 (7), 528-529; Hollander E, Managing aggressive behavior in patients with obsessive-compulsive disorder and borderline personality disorder, J. Clinical Psychiatry, 1999, 60 (Suppl), 1538-1544; Cora-Locatelli G, et. al., Gabapentin augmentation for fluoxetine-treated patients with obsessive-compulsive disorder [lefter], J. Clinical Psychiatry, 1998, 59 (9), 480-481; Koopowitz L F and Berk M, Response of obsessive compulsive disorder to carbamazepine in two patients with comorbid epilepsy, Annals of Clinical Psychiatry, 1997, 9 (3), 171-173).
According to the recent National Comorbidity Study (Anxiety Overview, Market Research Reports, 2001), social phobia (both global and specific) occurs in 13.3% of the population, one of the highest among anxiety disorders and the most misunderstood. Social phobia, if left untreated, will become associated with extensive morbidity and disability, leading to lifelong impairment in social development and occupational functioning. In global social phobia, all social situations are poorly tolerated, while specific social phobia includes performance anxiety or well-delineated phobia. Although the primary intervention for social phobia is environmental, pharmacological interventions have been shown to be effective in the treatment of social phobia. MAOIs can be effective in the treatment of social phobia, but it is unclear whether their effect arises from a primary effect on social phobia or from improved attention ability allowing for a better coping response. Central serotonergic dysregulation and abnormalities in dopaminergic function are believed to be associated with social phobia (Stein M B, Neurobiological perspectives on social phobia: From affiliation to zoology, Biol. Psychiatry, 1998, 44 (12), 1277-1285). Currently marketed drugs such as clonazepam and diazepam can relieve symptoms, but they also have side effects that are characteristic of the benzodiazepine class of drugs (that is, sedation and impairment of cognition and psychomotor performance). Nevertheless, anticonvulsants have been evaluated for the treatment of social phobia and have produced clinical benefit (Jefferson J W, Benzodiazepines and anticonvulsants for social phobia (social anxiety disorder), J. Clin. Psychiatry, 2001, 62 (Suppl. 1), 50-53; Connor K M, et. al., Social phobia: issues in assessment and management, Epilepsia, 1999, 40 (Suppl 6), S60-65, discussion S73-74).
Post Traumatic Stress Disorder (PTSD) is defined by the presence of a set of psychiatric symptoms triggered by a severely stressful event and is characterized by “re-experiencing” the traumatic event (eg, military combat, rape, child abuse, severe burns and witnesses to a peer suicide) along with decreased responsiveness and avoidance of current events associated with the trauma. The psychiatric symptoms are 3 core symptom clusters: intrusive thoughts (i.e. “re-experiencing” events, flashbacks, nightmares, etc.), avoidance behaviors and hyperarousal. Some of these core symptoms are clinically indistinguishable or highly similar to sensory seizures in epilepsy.
Acute psychological stress is the presumed immediate cause of PTSD, resulting in physiologic hyperarousal (startle reactions, intrusive thoughts, illusions, overgeneralized associations, sleep problems, nightmares, dreams about the precipitating event, impulsivity, difficulties in concentration, and hyper-alertness).
Clinical evidence supports that the flashbacks in PTSD represent an amalgam of abnormal neuronal firing along with the expression of a dynamically charged event (Brodsky L, Post traumatic stress disorder: an eclectic approach, International Journal of Psychosomatics, 1990, 37 (1-4), 89-95).
Anticonvulsants with a broad spectrum of activity most likely act to decrease the number and intensity of seizures and PTSD symptoms by regulating abnormal neuronal discharge patterns (Brodsky L, Post traumatic stress disorder: an eclectic approach, International Journal of Psychosomatics, 1990, 37 (1-4), 89-95). Based on this unique pathophysiology relevant to trauma-related alterations in arousal and memory, anticonvulsants are expected to prove effective in treating PTSD due to the anti-kindling/anti-sensitization and neurostabilizing properties of this class of drugs (Adamec R and Shallow T, Effects of baseline anxiety on response to kindling of the right medial amygdala, Physiol. Behav., 2000, 70 (1/2), 67-80; Friedman M J, What might the psychobiology of posttraumatic stress disorder teach us about future approaches to pharmacotherapy? J. Clin. Psychiatry, 2000, 61(Suppl. 7), 44-51; Stam R, et. al., Long-lasting stress sensitisation, Eur. J. Pharmacol. 2000, 405 (1-3), 217-224; Southwick S M, Role of norepinephrine in the pathophysiology and treatment of posttraumatic stress disorder, Biol. Psychiatry, 1999, 46 (9), 1192-1204).
Indeed, several anticonvulsant drugs such as carbamazepine, valproate and lamotrigine all have shown efficacy in PTSD (Hertzberg M A, A preliminary study of lamotrigine for the treatment of positraumatic stress disorder, Biological Psychiatry, 1999, 45 (9),1226-9; Davidson J R, Biological therapies for posttraumatic stress disorder: an overview, J. Clinical Psychiatry, 1997, 58 (Suppl), 929-32; Friedman M J, Drug treatment for PTSD: Answers and questions, Annals of the New York Academy of Sciences, 1997 (June 21), 821359-71; Ford N, The use of anticonvulsants in posttraumatic stress disorder: case study and overview, J. Traumatic Stress, 1996, 9 (4), 857-63; Sutherland S M and Davidson J R, Pharmacotherapy for post-traumatic stress disorder, Psychiatric Clinics of North America, 1994, 17 (2), 409-23; Keck P E Jr., Valproate and carbamazepine in the treatment of panic and posttraumatic stress disorders, withdrawal states, and behavioral dyscontrol syndromes, J. of Clinical Psychopharmacology, 1992, 12 (1 Suppl), 36S-41S).
Clinical evidence further shows support for several anticonvulsant drugs (such as carbamazepine, divalproex sodium, gabapentin, lamotrigine, topiramate and vigabatrin) having efficacy in the treatment of PTSD symptoms (Berigan, T R., Holzgang A, Valproate As An Alternative In Post-Traumatic Stress: A Case Report, Military Medicine, 1995, 160(6):318; Berlant J. Topiramate In Chronic Civilian PTSD—An Open-Label Study of a Novel Treatment, International Society for Traumatic Stress Studies, Melbourne, Australia, 2000; Brannon N, Labbate L, Huber M, Gabapentin Treatment For Posttraumatic Stress Disorder, Canadian J. Psychiatry, 2000, 45(1):84; Brodsky L, Doerman A L, Palmer L S, Slade G F, Munasifi F A, Post Traumatic Stress Disorder: An Eclectic Approach, Int. J. Psychosomat, 1990, 37(1-4):89-95; Clark, R D, Divalproex In Postraumatic Stress Disorder: An Open-Label Clinical Trial, J. Trauma. Stress, 1999, 12(2):395-401; Fesler, F A, Valproate In Combat-Related Posttraumatic Stress Disorder, J. Clin. Psychiatry, 1991, 52(9):361-364; Hertzberg M A, Blutterfield M I, Feldman M E et al, A Preliminary Study of Lamotrigine for the treatment of Positraumatic Stress Disorder, Biol. Psychiatry, 1999, 45:1226-1229; Lipper S, Davidson J R T, Grady T A et al, Preliminary Study Of Carbamazepine In Posttraumatic Stress Disorder, Psychosomatics, 1986, 27(12):849-854; Looff D, Grimley P, Kuller F, Martin A, Schonfield L, Carbamazepine for PTSD, J. Am. Acad. Child Adolesc. Psychiatry, 1995, 34(6):703-704; MacLeod, A D, Vigabatrin and Posttraumatic Stress Disorder, J. Clin. Psychopharmacol, 1996, 16(2):190-191; Szymanski H V, Olympia J, Divalproex In Posttraumatic Stress Disorder, Am. J. Psychiatry, 1991, 148(8):1086-1087, Wolf M E, Alavi A, Mosnaim A D, Posttraumatic Stress Disorder In Vietnam Veterans: Clinical, Biol. Psychiatry, 1998, 23:642:644).
The lifetime prevalence of any anxiety disorder is 24.9%. This number represents 15 to 20% of all medical clinic patients. Only 27% of such individuals have received effective treatment (National Institute of Mental Health, 2001).
Substituted phenyl alkyl carbamate compounds have been described in U.S. Pat. No. 3,265,728 to Bossinger, et al (hereby incorporated by reference), as useful in treating the central nervous system, having tranquilization, sedation and muscle relaxation properties of the formula: wherein R1 is either carbamate or alkyl carbamate containing from 1 to 3 carbon atoms in the alkyl group; R2 is either hydrogen, hydroxy, alkyl or hydroxy alkyl containing from 1 to 2 carbons; R3 is either hydrogen or alkyl containing from 1 to 2 carbons; and X can be halogen, methyl, methoxy, phenyl, nitro or amino.
A method for inducing calming and muscle relaxation with carbamates has been described in U.S. Pat. No. 3,313,692 to Bossinger, et al (hereby incorporated by reference) by administering a compound of the formula: in which W represents an aliphatic radical containing less than 4 carbon atoms, wherein R1 represents an aromatic radical, R2 represents hydrogen or an alkyl radical containing less than 4 carbon atoms, and X represents hydrogen or hydroxy or alkoxy and alkyl radicals containing less than 4 carbon atoms or the radical: in which B represents an organic amine radical of the group consisting of heterocyclic, ureido and hydrazino radicals and the radical —N(R3)2 wherein R3 represents hydrogen or an alkyl radical containing less than 4 carbon atoms.
Optically pure forms of halogen substituted 2-phenyl-1,2-ethanediol monocarbamates and dicarbamates have also been described in U.S. Pat. No. 6,103,759 to Choi, et al (hereby incorporated by reference), as effective for treating and preventing central nervous system disorders including convulsions, epilepsy, stroke and muscle spasm; and as useful in the treatment of central nervous system diseases, particularly as anticonvulsants, antiepileptics, neuroprotective agents and centrally acting muscle relaxants, of the formulae: wherein one enantiomer predominates and wherein the phenyl ring is substituted at X with one to five halogen atoms selected from fluorine, chlorine, bromine or iodine atoms and R1, R2, R3, R4, R5 and R6 are each selected from hydrogen and straight or branched alkyl groups with one to four carbons optionally substituted with a phenyl group with substituents selected from the group consisting of hydrogen, halogen, alkyl, alkyloxy, amino, nitro and cyano. Pure enantiomeric forms and enantiomeric mixtures were described wherein one of the enantiomers predominates in the mixture for the compounds represented by the formulae above; preferably one of the enantiomers predominates to the extent of about 90% or greater; and, most preferably, about 98% or greater.
Halogen substituted 2-phenyl-1,2-ethanediol carbamate compounds of Formula (I) or Formula (II) have not been previously described as useful for preventing or treating anxiety disorders. Recent preclinical studies have revealed previously unrecognized pharmacological properties which suggest that a compound of Formula (I) or Formula (II) is useful in preventing or treating anxiety disorders. Therefore, it is an object of the present invention to teach a method for use of a compound of Formula (I) or Formula (II) in preventing or treating anxiety disorders.